Curative Conversion of Metastatic Gastric Cancer After Pembrolizumab-Trastuzumab-Based Therapy in a PD-L1-Negative, HER2-Positive Patient: A Case Report and Literature Review

Abstract

Introduction
Metastatic gastric cancer (mGC) is a challenging malignancy with poor survival outcomes. Immune checkpoint inhibitors (ICIs), including pembrolizumab, have shown promise in improving responses, particularly in Programmed Death-Ligand 1 (PD-L1)-positive and Microsatellite Instability (MSI)-high tumours. However, based on trial data, only patients with PD-L1-high (Combined Positive Score (CPS) ≥1) or microsatellite-unstable tumours are expected to derive benefit from ICIs.
Case Presentation
We report a 60-year-old male who presented with epigastric pain, early satiety, and significant weight loss. Esophagogastroduodenoscopy revealed an ulcerated gastric mass, and biopsy confirmed poorly differentiated gastric adenocarcinoma. Staging investigations demonstrated metastatic disease with omental, peritoneal, and distant nodal involvement (cT4N3M1). Immunohistochemistry showed strong HER2 positivity (IHC 3+), PD-L1 negativity (CPS <1), and proficient mismatch repair (pMMR). He was treated with pembrolizumab and trastuzumab-based chemotherapy. Following nine cycles, imaging revealed near complete radiological response. The patient underwent radical total gastrectomy, splenectomy, omentectomy, and perigastric lymphadenectomy and pathological examination confirmed a complete pathological response (ypT0N0). The patient remains disease free at 28 months post-resection.
Discussion
This case demonstrates pembrolizumab’s efficacy beyond PD-L1 expression, this is in keeping with previously reported responses in PD-L1-negative patients. The contribution of trastuzumab and cytotoxic agents to the observed response cannot be excluded, as pembrolizumab is not expected to confer benefit in CPS-negative disease per current trial evidence. Conversion surgery, facilitated by systemic therapy, exemplifies a promising approach to improving outcomes in advanced mGC.
Conclusion
The clinical course observed in this patient suggests that the incorporation of pembrolizumab alongside chemotherapy and targeted therapy may be associated with significant tumour downstaging in select cases of advanced metastatic gastric cancer, even in the setting of PD-L1–negative disease. While causal inference cannot be drawn from a single case, this observation highlights the need for further translational and clinical studies to better understand the biological factors that may underlie such atypical responses.